High-resolution deconvolution of selection effects on the composition of the B cell repertoire

项目摘要 V(D)J重组的随机性，其主要目的是产生与广泛的 一系列潜在的靶点，通常会不经意地产生识别自身抗原的抗体。是这样的 自身反应性抗体通常与自身免疫性疾病有关，这些疾病会对人的健康产生不利影响 数百万人，给社会带来了巨大的财政负担。在早期发展过程中，机制是存在的 用于管理自身反应性B细胞，包括删除、修改或沉默。在外周，B细胞 亲和力成熟受制于外周耐受机制，以防止获得高 亲和力自身反应性。事实上，横跨整个B国的无数选择和容忍机制 从早期的前B细胞到长寿的浆细胞，对细胞的组成产生了巨大的影响 人类抗体库。尽管选择和容忍的曲目塑造效果被认为是 相当大，我们对B细胞谱系组成的方式仍然只有有限的了解 由选择决定的。 本实验室的长期研究重点是使用高通量测序来获得更完整的 了解人类B细胞库的发育、成熟和功能。继续 技术进步，包括新兴的单细胞分析技术，使构建 大量单个细胞的日益详细的分子图谱。极高的分辨率 这样的数据集将使体液免疫系统的研究达到前所未有的深度和细节水平。 在接下来的五年里，我们将利用这些进步来解决 以下是几个方面。(1)发现由B细胞受体编码的特定特征或特征模式 通过中心耐受性选择性地耗尽或改变的。(2)确定早期B细胞发育检查点 在这种情况下，选择和容忍使不同个体的曲目同质化。(3)人物特征 亲和力成熟的全球模式，独立于任何特定的抗原，全球塑造 记忆剧目的组成。更全面地了解以下过程和机制 塑造B细胞谱系是至关重要的，并与正在进行的传染病研究广泛相关， 自身免疫和合理的疫苗开发。

Project Summary The random nature of V(D)J recombination, whose primary purpose is to produce antibodies that bind a broad range of potential targets, often inadvertently creates antibodies that recognize self antigens. Such autoreactive antibodies are often associated with autoimmune diseases that adversely affect the wellbeing of millions and represent a significant financial burden on society. During early development, mechanisms exist for managing autoreactive B cells, including deletion, modification, or silencing. In the periphery, B cells undergoing affinity maturation are subject to peripheral tolerance mechanisms to prevent acquisition of high affinity autoreactivity. Indeed, a myriad of selection and tolerance mechanisms, spanning the entirety of the B cell lineage from early pro-B cells to long-lived plasma cells, exert massive influence on the composition of the human antibody repertoire. Although the repertoire-shaping effects of selection and tolerance are thought to be quite large, we still have only a limited understanding of the ways in which B cell repertoire composition is regulated by selection. The long-term research focus of my laboratory is to use high-throughput sequencing to gain a more complete understanding of the development, maturation and function of the human B cell repertoire. Continuing technological advances, including emerging single-cell analysis techniques, allow the construction of increasingly detailed molecular profiles for large numbers of individual cells. The extremely high resolution of such datasets will allow study of the humoral immune system at an unprecedented level of depth and detail. Over the next five years, we will leverage these advances to address significant knowledge gaps in the following areas. (1) Discovery of specific features or feature patterns encoded by B cell receptors that are selectively depleted or modified by central tolerance. (2) Identification of early B cell development checkpoints at which selection and tolerance homogenize the repertoires of different individuals. (3) Characterization of global patterns of affinity maturation which, independent of any particular antigen, globally shape the composition of the memory repertoire. A more complete understanding of the processes and mechanisms that shape the B cell repertoire is vitally important and broadly relevant to ongoing research in infectious disease, autoimmunity, and rational vaccine development.